The synthesis of the insect pheromone (2S,3R,7R)-3,7-dimethyltridec-2-yl acetate from racemic 3,4-dimethyl-γ-butyrolactone by diastereoselective chiral resolution

Article abstract of DOI:10.1016/j.tetasy.2006.11.005

The insect pheromone (2S,3R,7R)-3,7-dimethyltridec-2-yl acetate 1-Ac was prepared from diastereomerically enriched (2S^*,3R^*,7R)-1, which in turn was obtained by the coupling of racemic 3,4-dimethyl-γ-butyrolactone with (7S)-2-methyloctyllithium, followed by a Wolff-Kishner reduction of the resulting ketone. Conversion of (2S^*,3R^*,7R)-1 to the corresponding alkyl hydrogen phthalate and diastereomer salt formation with (S)-PhCHMeNH₂ provided after several crystallizations individual diastereomer, which was later transformed into target 1-Ac after hydrolysis and acylation.

Full text of DOI:10.1016/j.tetasy.2006.11.005

Tetrahedron: Asymmetry 17 (2006) 2976–2980
The synthesis of the insect pheromone
(2S,3R,7R)-3,7-dimethyltridec-2-yl acetate from racemic
3,4-dimethyl-c-butyrolactone by diastereoselective chiral resolution
Konstantin N. Prokhorevich and Oleg G. Kulinkovich*
Department of Organic Chemistry, Belarusian State University, Nezavisimosty Avenue 4, 220030 Minsk, Belarus
Received 20 September 2006; accepted 1 November 2006
Abstract—The insect pheromone (2S,3R,7R)-3,7-dimethyltridec-2-yl acetate 1-Ac was prepared from diastereomerically enriched
(2S*,3R*,7R)-1, which in turn was obtained by the coupling of racemic 3,4-dimethyl-c-butyrolactone with (7S)-2-methyloctyllithium,
followed by a Wolff–Kishner reduction of the resulting ketone. Conversion of (2S*,3R*,7R)-1 to the corresponding alkyl hydrogen
phthalate and diastereomer salt formation with (S)-PhCHMeNH2 provided after several crystallizations individual diastereomer, which
was later transformed into target 1-Ac after hydrolysis and acylation.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
tion of enantiomers of secondary alcohols4 for the separa-
tion of (2S,3R,7R)-1 from (2S*,3R*,7R)-1. The latter was
prepared by the Hedenstro¨m approach1 started from a
racemic trans-3,4-dimethyl-c-butyrolactone 2.
Pine sawfly (Diprion pini L.) is a widespread pest of
pine forests in Europe, Asia and North America, the sex
pheromone of which is the acetate of (2S,3R,7R)-3,7-
dimethyltridecan-2-ol 1-Ac.1 Individual (2S,3R,7R)-3,7-
dimeth- yltridecan-2-ol 1 was first synthesized starting from
(R)-(ꢀ)-2-methyloctanoic acid1 and (3R,4R)-3,4-dimethyl-
c-butyrolactone 2. The latter was obtained with a high
enantiomeric excess in 10 steps from (2R,3R)-tartaric acid,
whereas (R)-(ꢀ)-2-methyloctanoic acid was synthesized
over two consecutive lipase catalyzed esterifications of
racemic 2-methyloctanoic acid. The desired configuration
of alcohol 1 at the C2 carbon atom was obtained after
Mitsunobu inversion at the last step of the synthesis.1
Hedenstro¨m et al.2 have performed the synthesis of
(2S,3R,7R/S)-1, based on the resolution of racemic
(2S*,3R*,7R/S)-3,7-dimethyltridecan-2-ol 1 by enantio-
selective enzymatic acylation. Recently, we have reported
the successful separation of (2S,3R,7R/S)-1 from a mixture
of diastereomers (2S,3R/S,7R/S)-1 by their conversion to
alkyl hydrogen phthalates followed by recrystallization of
the salts obtained and hydrolysis.3 Herein we report the
successful utilization of this classical method for the resolu-
2. Results and discussion
3,4-Dimethyl-c-butyrolactone 2 with a diastereomeric ratio
of trans/cis = 1.5:1 was obtained by a free radical addition
of ethanol to ethyl crotonate with subsequent lactoniza-
tion.5 Heating compound 2 with perchloric acid without
a solvent at 100 ꢁC for 3 days led to the formation of the
equilibrating mixture,6 consisting of nearly 85% trans-dia-
stereomer. Coupling of lactone 2 with a chiral alkyllithium
3 led to the formation of ketoalcohol 4 with a ratio of
S*R*/S*S* = 5.5:1. Wolff–Kishner reduction7 of the latter
gave alcohol (2S*,3R*,7R)-1 with the same diastereomeric
composition (Scheme 1). Preparation of the alkyl hydrogen
phthalate 5 and its salt with (S)-(ꢀ)-PhCHMeNH2 68,9 pro-
vided, after 10 recrystallizations from acetone, the individ-
ual (2S,3R,7R)-diastereomer 63 (de = 98%) in 32% yield
from the alcohol (2S*,3R*,7R)-1 (after five recrystalliza-
tions the yield was 36%, de = 92%). Decomposition of salt
(2S,3R,7R)-6 and basic hydrolysis of alkyl hydrogen phth-
alate 7 in methanol led to the chiral alcohol (2S,3R,7R)-1,
the acylation of which furnished the target pheromone
(2S,3R,7R)-1-Ac in a total yield of 18% starting from lac-
tone 2. The (S)-configuration at the C-2 atom (>99.5%)
*
Corresponding author. Tel.: +375 17 2095459; fax: +375 17 2265609;
e-mail: kulinkovich@bsu.by
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.11.005

K. N. Prokhorevich, O. G. Kulinkovich / Tetrahedron: Asymmetry 17 (2006) 2976–2980
2977
Li
C6H13
(t-BuO)2
3
+
CO2Et
EtOH
O
65%
57%
O
rac-2
trans/cis = 1.5/1
H+
85%
trans/cis = 5.5/1
1: (S)-PhCHMeNH2
2: 10 recrystallizations
OR
OH
N2H4, KOH
90%
C6H13
C6H13
33%
O
(2S*,3R*,7R)-1: R = H
5: R = o-COC6H4CO2H
4
99%
o-C6H4(CO)2O, Et3N
2S*3R*/2S*3S* = 5.5/1
*
o-
O CC H CO H
(S)-PhCHMeNH2
2
6
4
2
OR
H+
Et3N, AcCl
OAc
3
7
C6H13
C6H13
C6H13
2
95%
99%
6
2S*3R*/2S*3S* = 100/1
2S/2R > 200/1
7: R = o-COC6H4CO2H
1-Ac
KOH
99%
1: R = H
Scheme 1.
was determined after derivatization of compound 1 to the
corresponding ester with (R)-(+)-Mosher’s acid and
comparison of the obtained H NMR spectrum with the
mide 12 under mild conditions,13 which in turn was synthe-
sized from ethyl heptanoate via cyclopropanol 13 and its
mesylate 14 by previously elaborated procedure.14 Conver-
sion of chiral alcohol 10 into chloride 8 was carried out by
the reaction of the corresponding mesylate with tetrabuty-
lammonium chloride.15
1
spectra of authetic samples of (2S,3R,7R/S)-3,7-dimethyl-
tridecan-2-ol and its Mosher esters.3,10
Chiral lithium reagent 3 was generated from chloride 8
according to Scheme 2. The key step of this reaction
sequence was the enantioselective reduction of acetal 9 to a
chiral alcohol 10 (ee 95%) by baker’s yeast Saccharomyces
cerevisiae.11,12 The stereochemical outcome was confirmed
by the comparison of the resonances of the CH2O moiety
3. Conclusion
Acetate 1-Ac, the sex pheromone of the pine sawfly D. pini,
has been prepared in its stereoisomerically pure form
from a racemic lactone 2 in a total yield of 18%. For the
enantioselective formation of methyl branches at C2, C3
and C7 in compound (2S,3R,7R)-1, the diastereomer salt
1
in the H NMR spectrum of the (R)-(+)-Mosher’s ester
with that published previously.11 The required unsaturated
aldehyde 11 was obtained by Kornblum oxidation of bro-
2.3 EtMgBr,
0.1 Ti(Oi-Pr)4
MgBr2
93%
DMSO, NaHCO3
71%
C6H13
C6H13CO2Et
C6H13
CH2Br
99%
99%
RO
12
13: R=H
MsCl, Et3N
14: R=Ms
baker's
yeast
HC(OEt)3, H+
80%
OEt
OEt
X
C6H13
C6H13
C6H13
CHO
11
9
10: X = OH
8: X = Cl
1. MsCl, Et3N
2. Bu4NCl
27%
from 9
Scheme 2.

2978
K. N. Prokhorevich, O. G. Kulinkovich / Tetrahedron: Asymmetry 17 (2006) 2976–2980
6 formation and the enantioselective reduction of the
carbon–carbon double bond in an unsaturated acetal of
a-methylenealdehyde 9 were used.
in dry diethyl ether (500 mL). The reaction mixture was
kept at room temperature overnight and then treated with
water (150 mL). The water phase was extracted with
diethyl ether (3 · 100 mL) and the combined organic
phases were washed with brine (100 mL), dried over
MgSO4 and concentrated to give the crude mesylate 14
(43.20 g, 99%), which was used without purification in
the next step. IR (CCl4), cmꢀ1: 3093, 1340, 1167, 1153;
1H NMR, d, ppm: 0.66 (t, J = 7.0 Hz, 2H, H-2, H-3),
0.85 (t, J = 6.7 Hz, 3H, CH3), 1.20 (t, J = 7.0 Hz, 2H,
H-2, H-3), 1.23–1.36 (m, 6H, (CH2)3), 1.44–1.54 (m, 2H,
CH2), 1.77–1.84 (m, 2H, CH2), 2.95 (s, 3H, OSO2CH3);
13C NMR, d, ppm: 11.6, 13.9, 22.4, 25.4, 28.8, 31.6, 35.8,
39.7, 66.9. C10H20O3S (220.3): calcd C, 54.51; H, 9.15.
Found: C, 54.58; H, 9.19.
4. Experimental
4.1. General
Commercially available chemicals were used without fur-
ther purification unless otherwise stated. Et2O (Na, benzo-
phenone), hexane (Na), benzene (Na), DMSO (CaH2) and
EtOH (CaH2) were distilled from the indicated drying
agents prior to use. Column chromatography was per-
formed on silica gel (Merk 60, 70–230 mesh) employing a
gradient technique using an increasing concentration of
diethyl ether in petroleum ether or of ethyl acetate in petro-
leum ether (0!20%), as eluent. Progress of the reaction
was monitored by thin layer chromatography, which was
performed on silica gel plates (Merk 60 F254) eluted with
ethyl acetate (20–40%) in cyclohexane. GC analyses were
carried out with a HP 5890 Series II gas chromatograph
with helium as a carrier gas and an HP-INNOWAX,
19095N-123 capillary column. Optical rotations were mea-
sured at 20 3 ꢁC with polarimeter CM-3 (scale fac-
tor = 0.05ꢁ). IR spectra were recorded with a Specord 75
4.2.3. 2-(Bromomethyl)oct-1-ene 12. A solution of MgBr2
prepared from magnesium turnings (9.72 g, 400 mmol) and
1,2-dibromoethane (75.2 g, 400 mmol) in dry diethyl ether
(250 mL) was added to a stirred and refluxed solution of
mesylate 14 (36.35 g, 165 mmol) in dry diethyl ether
(250 mL). The reaction mixture was stirred at reflux for
4 h and then quenched with water (300 mL). Extractive
workup with diethyl ether (3 · 150 mL) and brine
(50 mL), drying over MgSO4 and concentration followed
by distillation (bp 97 ꢁC, 16 mmHg) gave bromide 12
1
IR or Vertex 70 spectrometer. H and 13C NMR spectra
1
(31.42 g, 93%). IR (CCl4), cmꢀ1: 3080, 1640; H NMR, d,
were obtained with a Bruker AC 400 instrument at 400
ppm: 0.89 (t, J = 6.7 Hz, 3H, H-8), 1.23–1.35 (m, 6H,
(CH2)3), 1.46 (m, 2H, H-4), 2.21 (t, J = 7.6 Hz, 2H, H-3),
3.97 (s, 2H, CH2Br), 4.95 (m, 1H, H-1), 5.15 (m, 1H, H-
1); 13C NMR, d, ppm: 14.0, 22.6, 27.3, 28.9, 31.7, 33.3,
36.8, 114.7, 145.7. C9H17Br (205.1): calcd C, 52.70; H,
8.35. Found: C, 52.71; H, 8.36.
and 100 MHz, respectively, in CDCl3 (CHCl3 at d =
1
7.26 for H and d = 77.0 for 13C as an internal standard).
4.2. Synthesis of (2R)-1-chloro-2-methyloctane 8
4.2.1. 1-Hexylcyclopropanol 13. A solution of ethylmag-
nesium bromide (600 mmol) prepared from magnesium
turnings (14.6 g, 600 mmol) and ethyl bromide (65.4 g,
600 mmol) in diethyl ether (300 mL) was slowly added
dropwise with stirring to a solution of ethyl heptano-
ate (33.2 g, 210 mmol) and titanium tetraisopropoxide
(4.26 g, 15 mmol) in dry diethyl ether (200 mL).16 The reac-
tion mixture was then added with stirring and cooling to
sulfuric acid (20% aqueous solution, 310 mL) at such a
speed that the temperature did not exceed 10 ꢁC. Extractive
workup with diethyl ether (3 · 100 mL), NaHCO3 (aque-
ous saturated solution, 50 mL) and brine (100 mL), drying
over MgSO4 and concentration gave the crude cyclopropa-
nol 13 (29.60 g, 99%) which could be used without purifica-
tion for the next step. Pure cyclopropanol 13 was obtained
after distillation (28.41 g, 95%, bp 67–71 ꢁC, 2 mmHg). IR
(CCl4), cmꢀ1: 3593, 3327, 3080; 1H NMR, d, ppm: 0.43 (dd,
J = 6.5, 5.0 Hz, 2H, H-2, H-3), 0.72 (dd, J = 6.5, 5.0 Hz,
2H, H-2, H-3), 0.88 (t, J = 6.7 Hz, 3H, CH3), 1.23–1.38
(m, 6H, (CH2)3), 1.43–1.59 (m, 4H, (CH2)2), 1.91 (br s,
1H, OH); 13C NMR, d, ppm: 13.3, 14.0, 22.6, 25.8, 29.3,
31.8, 38.2, 55.6. C9H18O (142.2): calcd C, 76.00; H, 12.75.
Found: C, 76.05; H, 12.80.
4.2.4. 2-Hexylacrylaldehyde 11. A solution of allyl-
bromide 12 (29.66 g, 144.6 mmol) and NaHCO3 (20.70 g,
246 mmol) in dry DMSO (360 mL) was magnetically stir-
red at room temperature for 48 h with periodical removal
(every 1 h) of the resulting CO2 and Me2S in 15 mmHg vac-
uum. The mixture was then diluted with water (1.0 L) and
extracted with petroleum ether (4 · 250 mL). Evaporation
of the solvent, and column chromatography gave aldehyde
1
11 (14.45 g, 71%). IR (CCl4), cmꢀ1: 3080, 1690, 1633; H
NMR, d, ppm: 0.83 (t, J = 6.8 Hz, 3H, CH3), 1.19–1.31
(m, 6H, (CH2)3), 1.40 (m, 2H, CH2); 2.19 (t, J = 7.7 Hz,
2H, (CH2)), 5.94 (s, 1H, H-3), 6.20 (s, 1H, H-3), 9.49 (s,
1H, H-1); 13C NMR, d, ppm: 13.9, 22.5, 27.6, 27.7, 28.8,
31.5, 133.7, 150.4, 194.6. C9H16O (140.2): calcd C, 77.09;
H, 11.50. Found: C, 77.15; H, 11.54.
4.2.5. 2-(Diethoxymethyl)oct-1-ene 9. A solution of alde-
hyde 11 (14.02 g, 100 mmol), triethyl orthoformate (14.8 g,
100 mmol) and NH4NO3 (0.1 g) in dry ethanol (30 mL)
was stirred at 50 ꢁC for 8 h. The mixture was concen-
trated and subjected to column chromatography to give
1
acetal 9 (17.21 g, 80%). IR (CCl4), cmꢀ1: 1647; H NMR,
d, ppm: 0.88 (t, J = 7.1 Hz, 3H, H-8), 1.21 (t, J = 7.0 Hz,
6H, CH3CH2O), 1.19–1.37 (m, 6H, (CH2)3), 1.46 (m, 2H,
H-4), 2.06 (t, J = 7.8 Hz, 2H, H-3), 3.45 (dd, J = 9.4,
7.0 Hz, 2H, OCH2Me), 3.59 (dd, J = 9.4, 7.0 Hz, 2H,
OCH2Me), 4.73 (s, 1H, CH(OEt)2), 4.98 (m, 1H, H-1),
5.17 (m, 1H, H-1); 13C NMR, d, ppm: 14.0, 15.1, 22.6,
4.2.2. 1-Hexylcyclopropyl methanesulfonate 14. A solu-
tion of methanesulfonyl chloride (25.2 g, 220 mmol) in
diethyl ether (100 mL) was added dropwise with stirring
and cooling at 0 ꢁC to the solution of cyclopropanol 13
(28.16 g, 198 mmol) and triethylamine (25.3 g, 250 mmol)

K. N. Prokhorevich, O. G. Kulinkovich / Tetrahedron: Asymmetry 17 (2006) 2976–2980
2979
27.6, 29.1, 30.7, 31.7, 61.4, 103.3, 112.2, 146.5. C13H26O2
(214.3): calcd C, 72.85; H, 12.23. Found: C, 72.88; H,
12.2.
phase with NaHCO3 (aqueous saturated solution, 10 mL),
drying over MgSO4 and concentration furnished a dark
liquid, which after distillation (bp 100 ꢁC, 20 mmHg) gave
lactone 2 (1.53 g, 85%) with a trans/cis ratio of 85:15 by 1H
NMR. The 1H NMR spectral data corresponded to that re-
ported in the literature.5 13C NMR, d, ppm: 16.4, 18.8,
37.0, 37.9, 83.2, 176.3.
4.2.6. (2R)-2-Methyloctan-1-ol 10. A slightly modified
method of baker’s yeast mediated reduction12 was adapted
for the preparative scale synthesis. A solution of acetal 9
(17.14 g, 80.0 mmol) in ethanol (30 mL) was added por-
tionwise (in 12 portions over a period of 2 days) with stir-
ring at 34–38 ꢁC to the suspension of pressed baker’s yeast
(5000 g) in a buffer solution (pH ꢁ 5.25) of citric acid
monohydrate (75.6 g, 360 mmol) and NH4HCO3 (49.8 g,
630 mmol) in water (7.0 L). The reaction mixture was stir-
red for 3 days and sugar (3–5 g in 12–20 times a day) was
added. A yeast suspension was then subjected to steam dis-
tillation and the distillate (3 · 3 L) was carefully extracted
with petroleum ether (3 · 1 L), dried over Na2SO4 and con-
centrated to give crude alcohol 101 as a pale yellow liquid
(9.86 g, ꢁ86%, purity ꢁ60%), which was used without puri-
fication for the next step. The enantiomeric purity of 10
was 95% and was determined by comparison of 1H
NMR-spectra of the (+)- and (ꢀ)-MTPA-esters.10,11
4.3.2. (2S*,3R*,7R)-2-Hydroxy-3,7-dimethyltridecan-5-one
4. This compound was prepared from lactone 2 (1.43 g,
12.5 mmol) and (7S)-2-methyloctyllithium 3 according to
the previously described procedures.1 Column chromato-
graphy gave ketoalcohol 4 (1.96 g, 65%) with a S*R*/S*S*
1
ratio of 5:1 determined by H NMR. IR (CCl4), cmꢀ1
:
1
3613, 3447, 1713; H NMR, d, ppm: 0.74–0.80 (m, 9H,
CH3CH, CH3CH, H-13), 1.03 (d, J = 6.4 Hz, 0.5H, H-1),
1.09 (d, J = 6.3 Hz, 2.5H, H-1), 0.99–1.35 (m, 10H,
(CH2)5), 1.81–2.37 (m, 5H, CH2, H-3, H-7, OH), 2.44–
2.66 (m, 2H, CH2), 3.45 (app. quint, J = 6.3 Hz, 0.85H,
H-2), 3.68 (dq, J = 3.8, 6.4 Hz, 0.15H, H-2); 13C NMR,
d, ppm: 13.9, 16.5, 19.64, 19.67, 20.7, 22.4, 26.7, 29.0,
29.05, 29.3, 31.7, 31.8, 36.3, 36.7, 36.8, 46.7, 46.8, 50.75,
50.80, 71.5, 211.7.
4.2.7. (2R)-1-Chloro-2-methyloctane 8. A crude mesylate
of (2R)-2-methyloctan-1-ol (12.14 g) was prepared from
alcohol 10 (9.86 g) as above for 1-hexylcyclopropyl meth-
anesulfonate 14. Tetrabutylammonium chloride (18.04 g,
65.0 mmol) was added to a solution of mesylate of (2R)-
2-methyloctan-1-ol (12.14 g) in benzene (30 mL). The reac-
tion mixture was stirred at 70 ꢁC for 8 h, cooled to room
temperature and then quenched with water (60 mL). The
water phase was extracted with petroleum ether
(2 · 50 mL) and the combined organic phases were washed
with water (20 mL) and concentrated. The crude product
was diluted with n-hexane (60 mL), washed with concen-
trated sulfuric acid (3 · 15 mL), brine (10 mL), dried
4.3.3. (2S*,3R*,7R)-3,7-Dimethyltridecan-2-ol (2S*,3R*,
7R)-1. Wolff–Kishner reduction of ketoalcohol
4
(1.96 g, 8.1 mmol) in distilled triethanolamine7 (18 mL)
containing KOH (0.51 g, 9.1 mmol) and hydrazine mono-
hydrate (2.00 g, 40.0 mmol)1 furnished a yellow oil, which
after column chromatography gave the alcohol
(2S*,3R*,7R)-1 (1.66 g, 90%) with a S*R*/S*S* ratio of
5:1 by 1H NMR. IR (CCl4), cmꢀ1: 3633; 1H NMR, d,
ppm: 0.75–0.87 (m, 9H, CH3CH, CH3CH, H-13), 1.07 (d,
J = 6.4 Hz, 2.5H, H-1), 1.10 (d, J = 6.4 Hz, 0.5H, H-1),
0.97–1.53 (m, 18H, (CH2)8, H-3, H-7), 1.79–2.09 (br s,
1H, OH), 3.55–3.67 (m, 1H, H-2); 13C NMR, d, ppm:
14.0, 14.35, 14.37, 19.05, 19.1, 19.5, 19.6, 22.6, 24.6,
24.65, 26.95, 27.0, 29.6, 31.9, 32.64, 32.67, 32.8, 32.9,
36.9, 37.1, 37.25, 37.35, 39.90, 39.95, 71.50, 71.55.
(MgSO4) and concentrated. Title compound
8 was
obtained after distillation as a colourless liquid (3.48 g,
20
27% from acetal 9, bp 82 ꢁC, 16 mmHg). ½aꢂD ¼ þ3:3
(c 34.8, hexane). IR (CCl4), cmꢀ1: 2960, 2933, 2860, 687;
1H NMR, d, ppm: 0.88 (t, J = 6.8 Hz, 3H, H-8), 0.99 (d,
J = 6.6 Hz, 3H, CH3CH), 1.14–1.38 (m, 9H, (CH2)4, H-
3), 1.38–1.51 (m, 1H, H-3), 1.80 (m, 1H, H-2), 3.40 (dd,
J = 10.6, 6.2 Hz, 1H, H-1), 3.47 (dd, J = 10.6, 5.2 Hz,
1H, H-1); 13C NMR, d, ppm: 14.0, 17.7, 22.6, 26.8, 29.4,
31.8, 34.0, 35.5, 51.2. C9H19Cl (162.7): calcd C, 66.44; H,
11.77. Found: C, 66.48; H, 11.80.
4.4. Synthesis of (2S,3R,7R)-3,7-dimethyltridec-2-yl acetate
1-Ac
4.4.1. Salt of 2-({[(1S,2R,6R)-1,2,6-trimethyldodecyl]oxy}-
carbonyl)benzoic acid with (S)-(ꢀ)-1-phenylethylamine
6. Alcohol (2S*,3R*,7R)-1 (1.66 g, 7.3 mmol) was added
to a solution of o-phthalic anhydride (1.18 g, 8.0 mmol)
and triethylamine (1.82 g, 18.0 mmol) in dry benzene
(4 mL). The reaction mixture was stirred at 70 ꢁC for 3 h
and after cooling to room temperature, HCl (10% aqueous
solution, 20 mL) was added. The water phase was extracted
with benzene (4 · 30 mL), and the combined organic
phases were dried over MgSO4 and concentrated. The
crude phthalate 5 (2.74 g, 7.3 mmol) was added to a hot
solution of (S)-(ꢀ)-1-phenylethylamine (1.33 g, 11.0 mmol)
in acetone (50 mL). The solution was cooled to ꢀ10 ꢁC and
the crystalline salt was filtered off. After nine recrystalliza-
tions the title product was isolated (1.20 g, 33%, mp
4.3. Synthesis of (2S*,3R*,7R)-3,7-dimethyltridecan-2-ol
(2S*,3R*,7R)-1
4.3.1. trans-4,5-Dimethyldihydrofuran-2(3H)-one 2.
A
solution of ethyl crotonate (3.21 g, 28.1 mmol) and (t-
BuO)2 (2.06 g, 14.1 mmol) in absolute ethanol (25 g) was
heated to 170 ꢁC in a soldered high-pressure glass or steel
tube for 4 h.5 After cooling, the reaction mixture was con-
centrated and distilled (bp 99 ꢁC, 20 mmHg) to give lactone
2 (1.84 g, 16.1 mmol, 57%) with a trans/cis ratio of 60:40 by
1H NMR. Lactone 2 (1.80 g, 15.8 mmol) was heated with
HClO4 (72% aqueous solution, 0.5 mL) at 100 ꢁC for
3 days. After cooling, water (5 mL) was added. Extraction
with diethyl ether (3 · 20 mL), neutralization of the organic
1
121 ꢁC). IR (CCl4), cmꢀ1: 1713; H NMR, d, ppm: 0.81
(d, J = 6.3 Hz, 3H, CH3CH), 0.87 (t, J = 6.6 Hz, 3H, H-
12), 0.90 (d, J = 6.9 Hz, 3H, CH3CH), 1.13 (d, J =
6.2 Hz, 3H, CH3CH), 0.98–1.43 (m, 17H, (CH2)8, H-6),

2980
K. N. Prokhorevich, O. G. Kulinkovich / Tetrahedron: Asymmetry 17 (2006) 2976–2980
1.51 ðd; J ¼ 6:9 Hz; 3H; CHðNH3þÞCH3Þ, 1.69–1.79 (m,
1H, H-2), 4.26 ðq; J ¼ 6:7 Hz; 1H; CHðNH3þÞÞ, 4.90
ðbr s; 3H; –NH3þÞ, 7.18–7.29 (m, 3H, C6H5), 7.31–7.39
(m, 4H, C6H5, C6H4), 7.39–7.46 (m, 1H, C6H4), 7.60–7.66
(m, 1H, C6H4); 13C NMR, d, ppm: 14.1, 14.6, 15.5, 19.6,
21.3, 22.6, 24.7, 27.0, 29.6, 31.9, 32.7, 32.9, 37.0, 37.33,
37.35, 51.0, 74.7, 126.60, 127.67, 127.69, 127.9, 128.1,
128.5, 130.5, 130.7, 140.0, 140.3, 167.6, 174.5. C31H47NO4
(497.7): calcd C, 74.81; H, 9.52. Found: C, 74.85; H, 9.53.
1.12 (d, J = 6.4 Hz, 3H, H-1), 0.99–1.42 (m, 17H, (CH2)8,
H-7), 1.59–1.69 (m, 1H, H-3), 2.01 (s, 3H, CH3CO2), 4.79
(app. quint, J = 6.4 Hz, 1H, H-2); 13C NMR, d, ppm:
14.0, 14.5, 15.7, 19.7, 21.3, 22.6, 24.5, 27.0, 29.6, 31.9,
32.7, 32.9, 36.9, 37.2, 37.3, 74.2, 170.6. The 1H NMR
and 13C NMR spectral data corresponded to that reported
in the literature.1
(app.
quint,
J = 6.2 Hz,
1H,
H-1),
4.96–5.37
Acknowledgement
We are grateful for financial support from the Ministry of
Forest of the Republic of Belarus.
4.4.2. (2S,3R,7R)-3,7-Dimethyltridecan-2-ol (2S,3R,7R)-
1. Salt 6 (1.05 g, 2.1 mmol) was added to a mixture of
HCl (10% aqueous solution, 10 mL) and benzene
(50 mL). The organic phase was removed and the water
phase was extracted with benzene (3 · 50 mL). The com-
bined organic phases were dried over MgSO4 and concen-
trated to give phthalate 7 (0.78 g, 2.1 mmol, 99%), which
was added to a solution of KOH (1.12 g, 20.0 mmol) in
methanol (25 mL). The reaction mixture was refluxed for
3 h, diluted with water (70 mL) and extracted with diethyl
ether (3 · 50 mL), dried over MgSO4 and concentrated.
Title product 1 (0.48 g, 99%) was obtained as a colourless
liquid with a purity of >98% and a S*R*/S*S* ratio of
99.0:1.0 determined by GC. A purity of 99.5% with an
(S) configuration at C-2 atom was determined after deriv-
References
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Experimentia 1995, 51, 370–380, and references cited therein.
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Persson, D. J. Chem. Soc., Perkin Trans. 1 2002, 1810–1817.
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atization to the corresponding ester with (R)-(+) Mosher’s
20
acid by 1H NMR. ½aꢂD ¼ þ16:5 (c 4.8, hexane). IR (CCl4),
1
cmꢀ1: 3628; H NMR, d, ppm: 0.82 (d, J = 6.5 Hz, 3H,
CH3CH), 0.84 (d, J = 6.6 Hz, 3H, CH3CH), 0.86 (t,
J = 6.8 Hz, 3H, H-13), 1.09 (d, J = 6.2 Hz, 3H, H-1),
0.97–1.52 (m, 18H, (CH2)8, H-7, OH), 1.69–1.82 (m, 1H,
H-3), 3.63 (app. quint, J = 6.2 Hz, 1H, H-2); 13C NMR,
d, ppm: 14.0, 14.4, 19.2, 19.7, 22.6, 24.7, 27.0, 29.6, 31.9,
1
32.7, 32.9, 37.0, 37.3, 40.0, 71.6. The H NMR and 13C
NMR spectral data corresponded to that reported in the
literature.1
11. Ferraboschi, P.; Reza-Elahi, S.; Versa, E.; Rivolta, F. M.;
Santaniello, E. Synlett 1996, 1176–1178.
12. Ferraboschi, P.; Reza-Elahi, S.; Versa, E.; Rivolta, F. M.;
Santaniello, E. Tetrahedron: Asymmetry 1999, 10, 2639–2642.
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4.4.3. (2S,3R,7R)-3,7-Dimethyltridec-2-yl acetate 1-
Ac. This compound was prepared from (2S,3R,7R)-3,7-
dimethyltridecan-2-ol 1 (0.24 g, 1.1 mmol) by esterification
with acetyl chloride by a standard procedure.1 The crude
product was concentrated and subjected to column chro-
23
matography to give ester 1-Ac (0.27 g, 95%). ½aꢂD ¼ þ8:3
(c 2.7, hexane). IR (CCl4), cmꢀ1: 1733; 1H NMR, d,
ppm: 0.82 (d, J = 6.7 Hz, 3H, CH3CH), 0.85 (d,
J = 6.9 Hz, 3H, CH3CH), 0.86 (t, J = 6.8 Hz, 3H, H-13),